2-(n, n-di-loweralkyl-amino-loweralkyl)-1-[pyridyl-methylidene]-indene and process



amino or N-methyl-N-benzylamino groups. alkylene radicals of anN,N-lower alkyleneimino group tates Unite The present invention relatesto tertiary amino-lower alkyl-indenes. Primarily, it concerns3-[(2-pyridyl)-lower alkyl1-2-(tertiary amino-lower alkyl)-indenes, thesalts and quaternary ammonium compounds thereof.

A Z-pyridyl residue is preferably unsubstituted or may be substituted bylower aliphatic hydrocarbon radicals, such as lower alkyl, e.g. methylor ethyl, or by lower aliphatic hydrocarbonoxy radicals, such as loweralkoxy,

e.g. methoxy or ethoxy; The lower alkyl radical of the (2-pyridy1)loweralkyl group, which connects the 2-pyridyl portion with the indenenucleus, is represented, for example, by a lower alkylene radical havingfrom one to seven carbon atoms, e.g. methylene, 1,1-ethylene, 1,2

ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 2,2-

propylcne, 1,1-butylene, 2,2-butylene, 2,3-butylene, 1,4-

butylene, etc.

The lower alkyl portion of the tertiary amino-lower alkyl group,attached to the 2-position of the indene nucleus, may be represented bya lower alkylene radical containing from one to seven carbon atoms; suchalkylene radicals are, for example, methylene, 1,2-ethylene,l-methyl-1,2-ethylene, Z-methyl-LZ-ethylene, 1,3-propylene, 1-methyl-1,3-propylene, 1,4-butylene, l-methyl-1,4-butylene, or1,5-pentylene. The lower alkylene radical or part of it may also beincorporated into a heterocyclic ring system, such as a saturatedheterocyclic ring system, containing the tertiary amino group as a ringmember. Preferably, the lower alkyl portion of the tertiary amino-loweralkyl group separates the basic tertiary amino group from the 2-positionof the indene nucleus by two to three carbon atoms.

Tertiary amino groups are, for example, N,N-di-lower hydrocarbon-aminoor N,N-lower alkylene-imino groups. Lower hydrocarbon radicals of anN,N-di-lower hydrocarhon-amino group are, for example, lower alkyl,lower 'alkenyl, lower cycloalkyl, monocyclic carbocyclic aryl ormonocyclic carbocyclic aryl-lower alkyl radicals containing from one toseven carbon atoms, e.g. methyl, ethyl, 'propyl, isopropyl, butyl,isobutyl, pentyl, neopentyl, allyl, methallyl, cyclopentyl, cyclohexyl,phenyl or benzyl. These hydrocarbon radicals may contain furthersubstituents; free hydroxyl or lower alkoxy groups, e.g. methoxy orethoxy, maybe mentioned as examples of such substituents. Thus,N,N-di-lower hydrocarbon-amino groups are represented, for example, byN,N-dimethylamino, N- methyl-N-ethyl-amino, N,N-diethylarnino,N,N-dipropylamino, N,N-diisopropylamino, N-methyl-N-cyclopentyl- Thelower contain from four to six carbon atoms which may be arranged in acarbon atom chain, or such carbon atom chain may be interrupted by ahetero atom such as nitrogen, sulfur or oxygen, and thus form a loweraZa-, thiaor oxaalkyleneradical. Together with the nitrogen atom suchalkylene radicals represent, for example, pyrrolidino radicals, e.g.pyrrolidino or Z-methyl-pyrrolidino; piperidino radicals, e.g.piperidiuo, 2-methyl-piperidino, 4-methylpiperidino,3-hydroxy-piperidino, 3-acetoxy-piperidino or3-hydroxymethyl-piperidino; 'hexamethyleneimino, morpholino,thiamorpholino or piperazino radicals, e.g. 4- 'methyl-piperazino,4-hydroxyethyl-piperazino or 4-acetoxyethyl-piperazino. The tertiaryamino-lower alkyl ice methyl or al-rnethyl-4-piperidino radical.

The l-position of the indene nucleus is preferably unsubstituted, or, ifsubstituted, contains a hydrocarbon radical, particularly lower alkyl,e.g. methyl; or monocyclic aryl-lower alkyl, e.g. benzyl.

The aromatic portion of the indene nucleus may be unsubstituted or maycontain at least one substituent in any of the four positions availablefor substitution. Such substituents may be, for example, lower alkyl,e.g. methyl or ethyl; hydroxyl; etherified hydroxyl, such as loweralkoxy, e.g. methoxy or ethoxy, or lower alkylenedioxy, e.g.methylenedioxy; esterified hydroxyl, e.g. methoxycarbonyloxy,ethoxy-carbonyloxy or acetoxy, or halogen, e.g. fluorine, chlorine orbromine; mercapto; etherified mercapto, such as lower alkyl-rnercapto,e.g. methylmercapto or ethylrnercapto; nitro; amino, such as primaryamino, or tertiary amino, for example, N,N-di-lower alkyl amino, e.g.dimethylamino.

Salts of the compounds of this invention are, particularly,therapeutically acceptable acid addition salts with inorganic acids,such as mineral acids, for example, hydrohalic acids, e.g. hydrochloricor hydrobromic acid; sulfuric or phosphoric acids; or with organicacids, such as lower aliphatic monocarboxylic acids, e.g. formic,acetic, propionic, glycolic, lactic, pyruvic or similar acids; loweraliphatic dicarboxylic acids, e.g. oxalic, malonic, succinic, maleic,hydroxymaleic, dihydroxymaleic, fumaric, malic, tartaric, citric, orsimilar acids; monocyclic or bicyclic ,carbocyclic aryl-carboxylic orcarbocyclic aryl-lower aliphatic carboxylic acids, e.g. benzoic,cinnamic, mandelic, salicylic, 4-amino-salicylic, Z-phenoxybenzoic,2-acetoxybenzoic, or similar acids; monocyclic or bycyclic carbocyclicaryl-dicarboxylic acids, e.g. phthalic or similar acids; organicsulfonic acids, e.g. methane sulfonic, ethane sulfonic, hydroxyethanesulfonie, benzene sulfonic, toluene sulfonic or similar acids; or aminoacids, e.g. methionine, tryptophane, lysine, arginine, aspartic,glutamic or hydroxyglutamic acid. Particularly useful are the salts withlower aliphatic dicarboxylic acids, especially unsaturated loweraliphatic dicarboxylic acids, e,g. maleic, hydroxymaleic,dihydroxymaleic, or fumaric acid; or the hydroxy-lower aliphaticdicarboxylic acids, e.g. malic, tartaric or citric acid. Salts, whichmaybe prepared primarily for identification purposes, are particularlythose with acidic organic nitro compounds, e.g. picric, picto- Ionic orflavianic acid; or metal complex acids, e.g. phosfphotunstic,phosphomolybdic, chloroplatinic or Reinecke acid.

Quaternary ammonium compounds of the indene derivatives of thisinvention may be either monoor polyquaternary ammonium compoundsdepending on the conditions of the quaternization reaction and/ or thenumber of tertiary amino groups present. Quaternary ammonium compoundsare particularly those with aliphatic halides or sulfonates, such aslower alkyl halides, e.g. methyl chloride, methyl bromide, methyliodide, ethyl bromide or propyl chloride; or lower alkyl lower alkanesulfonates, e.g. methyl methane sulfonate or methyl ethane sulfonate.Also included as quaternary ammonium compounds are the correspondingquaternary ammonium hydroxides, or the salts of such hydroxides withacids, particularly with the organic acids mentioned hereinabove.

Depending on the number of asymmetric carbon atoms the indene compoundsof this invention may be obtained as mixtures of racemates, racemates orantipodes, the

3 separation of which will be discussed and illustrated hereinbelow.

The new compounds of this invention show antihistaminic effects and areintended to be used, for example, as antihistaminic agents to relievedisorders, especially those caused by an excess of histamine, such ashay fever, urticaria, allergies caused by food or plant pollen, etc.Especially valuable with respect to their antihistaminic activity arethe 2-(N,N-di-lower alkyl-amino-lower alkyl)- 3-[(2-pyridyl)-loweralkyl]-indenes, in which the arcmatic portion of the indene nucleus isunsubstituted or may contain one or several of the previously mentionedsubstituents, particularly methyl, methoxy, chlorine or bromine, and thetherapeutically useful acid addition salts thereof. This group ofcompounds may be represented by 2-(N,N-di-lower alkyl-amino-loweralkyl)-3[(2-pyridyl)-(R )methyl]-indenes, in which R represents hydrogenor lower alkyl, particularly methyl, and the N,N-dilower alkyl-aminogroup is separated from the indene nucleus by two to three carbon atoms,and in which the aromatic portion of the indene nucleus is preferablyunsubstituted or may contain one or several of the previously mentionedsubstituents, particularly methyl, methoxy, chlorine or bromine, and thetherapeutically acceptable salts with mineral acids or lower aliphaticdicarboxylic acids. Such compounds are, for example, the 2-(N,N-di-loweralkyl-amino-lower alkyl)-3-[l-(2-pyridyl)-ethyl]-indenes, in which theN,N-di-lower alkylamino group is separated from the indene ring by twoto three carbon atoms; an outstanding member of this series of indenecompounds is the 2-(2-dimethylaminoethyl)-3-[1-(2-pyridyl)-ethyl]-indeneof the formula:

HzC-CH- N lower alkyl)-indenes, in which the pyridyl and the lower alkylradical of the (4-pyridyl)-lower alkyl group have the above-givenmeaning, the tertiary amino-lower alkyl group is represented by theabove-given examples, and in which the aromatic portion of the indenenucleus is unsubstituted or substituted as previously demonstrated, andthe salts and quaternary ammonium compounds thereof. These compoundsexhibit antihistaminic effects and may be used as antihistaminic agentsto relieve disorders, particularly those caused by an excess ofhistamine, such as hay fever, urticaria, allergies caused by food orplant pollen, etc. A similar activity is shown by the corresponding3-[(3-pyridyl)-lower alkyl] -2-(tertiary amino-lower alkyl)-indenes, inwhich the tertiary amino-lower alkyl portion has the above-givenmeaning, the aromatic portion of the indene nucleus is unsubstituted orsubstituted as indicated above, and the pyridyl group may beunsubstituted or substututed as shown hereinabove, and in which thecarbon atom of the lower alkyl chain of the (3-pyridyl)-lower alkylportion, which is connected to the 3-pyridyl nucleus, is preferablyunbranched, and salts and quaternary ammonium compounds thereof.

The new compounds of this invention may be used as medicaments in theform of pharmaceutical preparations, which contain the new indenederivatives, including the racemates or antipodes, the salts or thequaternary ammonium compounds thereof in admixture with a pharmaceuticalorganic or inorganic, solid or liquid carrier suitable for enteral, e.g.oral, or parenteral administration.

To relieve allergic skin troubles, they may also be employed topically.For making up the preparations there can be employed substances which donot react with the new compounds, such as water, gelatine, lactose,starches, magnesium stearate, talc, vegetable oils, benzyl alcohols,gums, polyalkylene glycols or any other known carrier for medicaments.The pharmaceutical preparations may be in the solid form, for example,as capsules, tablets or dragees, in liquid form, for example, assolutions, e.g. isotonic saline solutions, or as suspensions oremulsions, or in the form of salves or creams for topicaladministration. If desired, they may contain auxiliary substances, suchas preserving agents, stabilizing agents, wetting or emulsifying agents,salts for varying the osmotic pressure or buffers, etc. They may alsocontain, in combination, other therapeutically useful substances.

The indene compounds of this invention may be prepared according toseveral procedures, the selection of which may also be determined by thenature of the lower alkylene radical linking the pyridyl portion to theindene nucleus.

Preferably, the compounds of this invention may be obtained byintroducing a (2-pyridyl)-lower alkyl radical into a 2-( tertiaryamino-lower alkyl)-indan-1-one compound or a salt thereof, and, ifdesired, converting a resulting salt into the free compound and/or, ifdesired, converting a free compound into a salt or a quaternary ammoniumcompound thereof.

For example, a 2-(tertiary amino-lower alkyl-indan-lone may be reactedwith a (2-pyridyl)-lower alkyl metal compound, in which the metal isselected from metal elements of group Ia of the periodic system, i.e.the alkali metals, such as sodium, potassium or, preferably, lithium.The reaction is carried out in the presence of an inert solvent, forexample, a hydrocarbon, such as an aliphatic hydrocarbon, e.g. hexane,or an aromatic hydrocarbon, e.g. benzene, toluene or xylene, or in anether, such as a di-lower alkyl ether, e.g. diethylether, or a cyclicether, e.g. tetrahydrofuran. If desired, the reaction mixture may becooled, or the temperature may be elevated, for example, to the boilingtemperature of the solvent. The reaction is preferably performed in theatmosphere of an inert gas, e.g. nitrogen.

The above-mentioned (2-pyridyl)-lower alkyl metal compounds,particularly the lithium compounds, may be formed by reacting a 2-loweralkyl-pjyridine with an aryl metal, particularly a phenyl lithium,compound, or with an aliphatic hydrocarbon metal compound, particularlya lower alkyl lithium compound, e.g., n-butyl lithium, in a solvent,such as a lower aliphatic hydrocarbon, e.g. hexane; an aromatichydrocarbon, e.g. benzene, toluene or xylene; or an ether, such as adi-lower alkyl ether, e.g. diethylether, or a cyclic ether, e.g.tetrahydro furan, preferably in the atmosphere of an inert gas, c.g.nitrogen.

If (2-pyridyl)-lower alkyl radicals are introduced, in which the loweralkyl radical contains more than one carbon atom, the (2-pyridyl)-loweralkyl radical is preferably attached to the indene nucleus through thecarbon atom of the lower alkyl radical, which is directly attached tothe Z-pyridyl nucleus; for example, 2-ethyl-pyridine, when reacted inthe form of its lithium compound, furnishes the l-(2-pyridyl)-ethylradical. This procedure is, therefore, especially suitable for thepreparation of the 3-[(2-pyridyl)-(R )methyl]-2-(tertiary amino-loweralkyl)-indenes, in which the radical R represents hydrogen or,particularly lower alkyl, such as methyl.

The above reaction of indan-l-one compounds with (2- pyridyl)-loweralkyl metal derivatives may furnish directly the desired3-[(2-pyridyl)-lower alkyl]-2-(tertiary amino-lower alkyl)-indenes, asthe intermediarily formed l-[(2-pyridyl)-lower alkyl]-2-(tertiaryamino-lower alkyl)-indan-l-ols may lose water under the conditions ofthe reaction and form the desired indene derivatives of this invention,particularly, if during the isolation procedure of the reaction productacidic conditions are used. a dehydration of the intermediate indan-l-olcompounds, if necessary, may also be achieved, for example, by treatmentwith an acid reagent, for example, a mineral acid, such as a hydrohalicacid, e.g. hydrochloric acid, or sulfuric acid, if desired, in thepresence of water and/or an organic solvent such as, for example,glacial acetic acid, or with an organic acid, e.g. oxalic or p-toluenesulfonic acid; an anhydride, e.g. acetic acid anhydride; or an acidhalide, e.g. phosphorus oxychloride or acetyl chloride, if desired, inan organic base, e.g. pyridine, and, if necessary, with heating.

This procedure may also be suitable for the preparation of the3-[(4-pyridyl)-lower alkyl] -2-(tertiary aminolower alkyl)-indenes,mentioned hereinbefore to have antihistaminic properties. Thus, when aZ-(tertiary aminolower alkyl)-indan-l-one is reacted with a(4-pyridyl).- lower alkyl metal compound, in which the metal is selectedfrom the PYEVlO! sly mentioned group of metals, according to theaforementioned procedure, the desired 3-[(4-pyridyl) loweralkyl]-Z-(tertiary amino-lower alkyl)-indenes can be obtained directlyor after dehydra tion of any intermediarily formed 1-[(4-pyridyl)-loweralkyl]-Z-(tertiary amino-lower alkyl)-indan-1-ol, which dehydration maybe carried out as outlined hereinbefore.

The 2-(tertiary amino-lower alkyl)-indan-l-one compounds used as thestarting materials in the above reaction are known or, if new, may beprepared according to methods used for manufacturing known analogs. Forexample, an a-benzyi-malonic acid ester, such as a lower alkyl, e.g.ethyl, or a heterocyclic, e.g. tetrahydropyranyl, ester, in which thebenzyl portion may be unsubstituted or substituted as outlinedhereinabove, may be reacted with a reactive ester formed by a tertiaryamino-lower alkanol, in which the tertiary amino group is separated fromthe hydroxyl group by at least two carbon atoms, and a strong inorganicor organic acid, such as, for example, a mineral acid, e.g.hydrochloric, hydrobromic, hydriodic or sulfuric acid, or a saltthereof, to produce an u-benzyl-a-(tertiary amino-lower alkyl)-rnal0nicacid ester, in which the tertiary amino group is separated from theot-carbon atom by at least two carbon atoms. This condensation reactionis preferaby carried out in the presence of a base, such as an alkalimetal lower alkanoate, e.g. lithium, sodium or potassium Inethanolate,ethanolate, propanolate, isopio anolate or tertiary butanolate. Theresulting malonic acid ester may be cyclized to the Z-(tertiaryamino-lower alkyl)-indan-1-one, in which the tertiary amino group isseparated from the indan-l-one nucleus by at least two carbon atoms.This cyclization may be carried out prior or after hydrolysis of theester groups, for example, under alkaline conditions, such as in thepresence of an aqueous alkali metal hydroxide, e.g. sodium or potassiumhydroxide, and decarboxylation of a carboxyl group, for example, byheating, if desired, in the presence of a mineral acid, e.g.hydrochloric or sulfuric acid; The cyclization may be carried out, forexample, by treatment with a strong Lewis acid, such as a strong mineralacid, e.g. anhydrous hydrofluoric, sulfuric or phosphoric acid, thelatter, for example, in the form of polyphosphoric acid, or borontrifiuoride, for example, in the form of the etherate, or aluminumchloride.

The Z-(tertiary amino-methyl)-indan-l-ones may be prepared by anotherroute, for example, by reacting indan-l-one with a secondary amine or asalt thereof in the presence of formaldehyde according to the Mannichprocedure. Secondary amines furnish the tertiary amino group disclosedhereinbefore; salts thereof are particularly inorganic acid additionsalts, for example, salts with mineral acids, e.g. hydrochloric,hydrobromic or sulfuric acid. The formaldehyde may be used in solution,e.g. in an aqueous solution, or as a polymer, for example, asparaformaldehyde, or an acetal, e.g. dimethoxymethane or diethoxyethane.The reaction is preferably carried out in the presence of a solvent, forexample, a lower alkanol,

e.g. methanol or ethanol, or an aqueous mixture thereof, and ifnecessary, in the presence of an acid, for example, a mineral acid, e.g.hydrochloric or sulfuric acid. The reaction may be completed by heating,and the resulting Z-(tertiary amino-methyl)-indan-1-one may be isolatedas the free base or as the salt thereof.

1- (Z-pyridyl -lower alkyl] -2-(tertiary amino-lower alkyl)-indan-1-0ls,in which the tertiary amino-lower alkyl group has the above-givenmeaning, and the salts thereof, formed as intermediates in the processfor the preparation of the corresponding indenes, may be isolated. Theyare new and are intended to be included within the scope of thisinvention. As the previously described corresponding indene compounds,these indan-l-ol derivatives,

alkyl-amino group is separated from the indan-l-ol nucleus by two tothree carbon atoms, and in which the aromatic portion of the indan-l-olnucleus is preferably unsubstituted or may contain one or several of thepreviously mentioned substituents, particularly methyl, methoxy,chlorine or bromine. The 1-[(2-pyridyl)-lower alkyl]-Z-(tertiaryamino-lower alkyl)-indan-l-ols may exist as mixture-s of thediastereoisomeric racemates, which mixtures may be separated into theracemates, and, if desired, resulting racemates may be resolved into theantipodes according to procedures known in the art.

l-[(4-pyridyl)-lo wer alkyl]-Z-(tertiary amino-lower alkyl)-indan-l-ols,which may be formed as intermediates, if a (4-pyridyl)-lower alkyl isintroduced into a Z-(tertiary amino-lower alkyl)-indan-l-one, are newand are intended to be included within the scope of this invention. Theyshow antihistaminic effects and may be used to remedy allergicdisorders.

A modification of the general procedure for the preparation of thecompounds of this invention, i.e. introduction of the (2-pyridyl)-loweralkyl radical into a Z-(tertiary amino-lower alkyl)-indan-1-one,com-prises reacting a 2- (tertiary amino-lower alkyl)-indan-l-one with a(2-pyridyl)-lower alkyl-Grignard reagent, whereby the desired 3 [(2pyridyl)-lower alkyl] 2 (tertiary amino lower alkyl)-indene may beobtained directly or after dehydra tion of an intermediarily formedindan-l-ol compound. A (2-pyridyl)-lower alkyl-Grignard reagent is, forexample, a (2-pyridyl)lower alkyl metal halide compound, in which themetal is selected from those metal elements of the groups 11a and 11b ofthe periodic system, which are capable of forming organo-metalliccompounds. Such metals are, for example, magnesium or zinc. The halogenatom in such a Grignard reagent may be a chlorine, bromine or iodineatom. The reaction of the indan-l-one derivative with the(2-pyridyl)-lower alkyl-Grignard reag ent may be carried out in thesolvent used for the preparation of the organo-metallic compound, whichis preferably diethyl ether, or in another solvent, for example, inanother ether, such as an aryl lower alkyl ether, e.g. anisole; or acyclic ether, e.g. tetra-hydrofuran or pdioxane; or an organic base,e.g. N-ethylmorpholine or pyridine. Other solvents, which may also beadded after the formation of the Grignard reagent and, if desired, afterthe removal of the solvent used for the formation of the Grignardreagent, are hydrocarbons, such as aromatic hydrocarbons, e.g. benzene,toluene or xylene, or aliphatic hydrocarbons, e.g. pentane or hexane.(2- pyridyD-lower alkyl magnesium halides, e.g. chlorides or bromides,are the preferred reagents. The reaction may be carried out undercooling, at room temperature, and may be completed by heating, forexample, to the boiling point of the solvent. An inert gas, such asnitrogen,

7 may be used to avoid any contact with atmospheric oxygen.

An intermediarily formed indan-l-ol compound may be converted to thedesired indene compound directly under the conditions of the reaction ormay be treated with a dehydration agent as previously shown.

The above-described procedure, using a (2-pyridyl)- lower alkyl-Grignardreactant, is especially suited for the preparation of those3-[(2-pyridyl)-lower alkyll-indene derivatives, in which the lower alkylgroup, connecting the Z-pyridyl radical with the indene ring, is notbranched.

at the methylene group attached to the pyridyl radical.

This modification of the general process may also be used for thepreparation of 3-[(4-pyridyl)-lower alkyl]-2- (tertiary amino-loweralkyl)-indenes, for example, by reacting a Z-(tertiary amino-loweralkyl)-indan-l-one with a (4pyridyl)-lower alkyl-Grignard compoundaccording to the above-given procedure.

In addition, the method may also be applied for the formation of3-[(3-pyridyl)- lower alkylJ-Z-(tertiary amino-lower alkyl)-indenes bysubstituting a (3-pyridyl)-lower alkyl-Grignard reagent 'for thecorresponding (4-pyridyl)-lower alkyl derivative.

A second generally applicable process for the manufacture of a morelimited group, the 3-[(2-pyridyl)-methyl]-2-(tertiary amino-loweralkyl)-indenes, comprises reacting a Z-(tertiary amino-loweralkyl)-indene containresulting 1- (2-pyridyl) -methylidene]-2-( tertiaryaminolower alkyl)-indene to the desired3-[(2-pyridyl)-methyl]-2-(tertiary amino-lower alkyl)-indene byreduction, and, if desired, carrying out the optional steps.

The reaction of the aldehyde reagent with the 2-( tertiary amino-loweralkyl)-indene compound is carried out according to the conditions usedin Claisen condensations, for example, in the presence of a condensingreagent and, preferably, in a solvent. A condensing reagent isparticularly an alkali metal salt-forming condensing reagent, such as analkali metal hydroxide, e.g. lithium, SOdlllll'l or potassium hydroxide,or an alkali metal lower alkanolate, e.g. lithium, sodium or potassiummethanolate, ethanolate, propanolate, isopropanolate or butanolate;these reagents are preferably used in a solvent, such as, for example, alower alkanol, e.g. methanol, ethanol, propanol, isopropanol or butanol.Similar reagents are, for example, alkali metal hydrides or amides, e.g.lithium, sodium or potassium hydride or amide, which reagents are usedin an inert solvent, such as, for example, an ether, e.g. p-dioxane ordiethyleneglycol dimethylether; or an aromatic hydrocarbon, e.g.benzene, toluene or xylene. Other non-metallic condensing reagents maybe, for example, quaternary ammonium hydroxides, e.g.benzyltrimethyl-amrnonium hydroxide. The reaction may be carried outunder cooling, at room temperature or at an elevated temperature and, ifnecessary, in the amosphere of an inert gas, e.g. nitrogen.

If necessary, any intermediarily formed 3-[(2-pyridyl)-hydroxy-methyl]-2-(tertiary amino lower alkyl) indene may be dehydratedacording to previously given methods, for example, by treatment with anacid, such asa mineral acid, e.g. hydrochloric or sulfuric acid.

The resulting 1-[(2-pyridyl) -methylidenel-Z-(tertiary amino-loweralkyl)-indene is converted into the desired 3-[(2-pyridyl) methyl]2-(tertiary amino-lower alkyl)- indene by reduction. A preferredprocedure is represented by the hydrogenation in the presence of acatalyst, such as a palladium catalyst, e.g. palladium on charcoal,where by care has to be taken that only one mole of hydrogen is absorbedand the pyridine nucleus is not hydrogenated simultaneously. Thereduction is carried out in a solvent, preferably in a non-acidicsolvent, such as, for example, a lower alkanol, e.g. methanol orethanol. It may also be carried out with hydrogen in statu nascendi,such as furnished by a metal or a metal amalgam in the presence of ahydrogen donor, e.g. aluminum amalgam in the presence of wet ether, etc.

The product resulting from the reduction procedure may be the desired3-[(2-pyridyl)-methyl] 2 (tertiary amino-lower alkyl)-indene, or thelatter may be obtained after rearrangement of a double bond in thereduction product. Treatment with a mineral acid, e.g. hydrochloric orsulfuric acid, or with a base, such as an alkali metal hydroxide, e.g.sodium or potassium hydroxide, or an alkali metal lower alkanolate, e.g.sodium or potassium Inethanolate or ethanolate, may bring about therearrange- .ment of double bond. These rearrangement reagents arepreferably used in the presence of solvents, such as, for example, wateror lower alkanols or aqueous mixtures thereof, depending on thesolubility and/or reactivity of "the reagent or the reactant.

The starting materials used in this procedure are known or may beprepared according to known methods. For example, a Z-(tertiaryamino-lower alkyl)-indan-l-one can be converted to the correspondingindan-l-ol by reduction, for example, by treatment with catalyticallyactivated hydrogen, such as hydrogen in the presence of a nickel, eg.Raney nickel, or a palladium, e.g. palladium on charcoal, catalyst; withhydrogen in statu nascendi, such as furnished by a metal or a metalamalgam in the presence of a hydrogen donor, with an alkali metalborohydride, -e.g. sodium borohydride; with an alkali metal aluminumhydride, e.g. lithium aluminum hydride, or with an alumi- 'num loweralkoxide in the presence of a lower alkanol according to theMeerwein-Ponndorf-Verley method, for example, with aluminum isopropoxidein isopropanol. A

"resulting Z-(tcrtiary amino-lower alkyl)-indan-l-ol is then dehydrated,for example, in the presence of an acid, such as a mineral acid, e.g.hydrochloric or sulfuric acid.

The above-described modification of the general procedure may also beused for the manufacture of 3-[(4- pyridyl)-methyl]-2-(tertiaryamino-lower alkyl) indenes by substituting in the above procedure theZ-pyridine carboxaldehyde by a 4-pyridine carboxaldehyde. Thecorresponding 3-[(3-pyridyl) methyl]-2-(tertiary aminoloweralkyl)-indenes may be prepared by treating a 2- (tertiary amino-loweralkyl)-indene, which contains a methylene group as a ring member of theS-membered portion of the indene nucleus, with a 3-pyridinecarboxaldehyde according to the previously described procedure.

The new compounds of this invention may be obtained as mixtures ofdiastereoisomeric compounds or the salts thereof, which may be separatedinto the individual racemic compounds, the salts or the quaternaryammonium compounds thereof on the basis of physicachemical difierences,such as solubility, for example, by fractionated crystallization, ifnecessary, of a derivative, e.g. salt or quaternary ammonium compoundthereof.

The racemates of the compounds of this invention may be resolved intothe optically active dand l-forms according to procedures known for theresolution of racemic compounds. For example, the free base of a racemicd, l-compound may be dissolved in a lower alkanol, e.g. methanol orethanol, and one of the optically active forms of an acid containing anasymmetric carbon atom, or a solution thereof, for example, in the, samealkanol or in water or in a mixture of such solvents, is then added,whereupon a salt can be isolated, which is formed by the opticallyactive acid with an optically active form of the base. Especially usefulas optically active forms of saltforming acids having an asymmetriccarbon atom are D- and L-tartaric acid; the optically active forms ofmalic, mandelic, camphor sulfonic or quinic acid may also be employed.The free and optically active base may be obtained from the resultingsalt according to methods known for the conversion of a salt into abase, for example, as outlined hereinbelow. An optically active base maybe converted into a-therapeutically useful acid addition salt with oneof the acids mentioned hereinbefore, or may be converted into aquaternary ammonium compound as described hereinbelow. The opticallyactive forms may also be isolated by biochemical methods.

The indene compounds of this invention may be obtained in the form ofthe free bases or as the salts thereof. A salt may be converted into thefree base, for example, by reaction with an alkaline reagent, such as anaqueous alkali metal hydroxide, e.g. lithium, sodium or potassiumhydroxide; an aqueous alkali metal carbonate, e.g. sodium or potassiumcarbonate or hydrogen carbonate; aqueous ammonia or ammonia in a loweralkanol, e.g. methanol or ethanol, solution. A free base may beconverted into its therapeutically useful acid addition salts byreaction with one of the inorganic or organic acids outlinedhereinbefore, for example, by treating a solution of the free base in alower alkanol, e.g. methanol, ethanol, propanol or isopropanol, anether, e.g. diethylether, or a lower alkyl lower alkanoate, e.g. methylor ethyl acetate, or in a mixture of such solvents, with the acid or asolution thereof. The salts may also be obtained as the hemihydrates,monohydrates, sesquihydrates or polyhydrates depending on the conditionsused in the formation of the salts. Monoor poly-salts may be formedaccording to the conditions used in the procedure for the preparation ofthe salts and/ or the number of salt-forming groups present.

The quaternary ammonium compounds of the indene derivatives of thisinvention may be obtained, for example, by reacting the tertiary basewith an ester formed by a hydroxylated lower hydrocarbon compound and astrong inorganic or organic acid. Hydroxylated lower hydrocarboncompounds contain from one to seven carbon atoms and the esters thereofare more especially those with mineral acids, e.g. hydrochloric,hydrobromic or hydriodic acid, or withstrong organic acids, such aslower alkane sulfonic acids, e.g. methane or ethane sulfonic acid. Suchesters are specifically lower alkyl halides, e.g. methyl chloride,methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyliodide, propyl chloride, etc.; or lower alkyl lower alkane sulfonates,e.g. methyl methane sulfonate or methyl ethane sulfonate. Thequarternizing reactions may be performed in the presence or absence of asolvent; under cooling, at room temperature or at an elevatedtemperature; at atmospheric pressure or in a closed vessel underpressure, and, if desired, in the atmosphere of an inert ags, e.g.nitrogen. Suitable solvents are more especially lower alkanols, e.g.methanol, ethanol, propanol, isopropanol, butanol or pentanol; loweralkanones, e.g. acetone or methyl ethyl ketone; or organic acid amides,e.g. formamide or dirnethylformamide.

Resulting quaternary ammonium compounds may be converted into thecorresponding quaternary ammonium hydroxides, for example, by reacting aquaternary ammonium halide with silver oxide or a quaternary ammoniumsulfate with barium hydroxide, by treating a quaternary ammonium saltwith an anion exchanger, or by electrodialysis. From a resultingquaternary ammonium base there may be obtained quaternary ammonium saltsby reaction with acids, for example, with those outlined hereinbeforefor the preparation of the acid addition salts. A quaternary ammoniumcompound may also be converted directly into another quaternary ammoniumsalt without the formation of the quaternary ammonium hydroxide; forexample, a quaternary ammonium iodide may be reacted with freshlyprepared silver chloride to yield the quaternaryammonium chloride, or aquaternary ammonium iodide may be converted into the correspondingchloride by treatment with hydrochloric acid in anhydrous methanol.Quaternary ammonium compounds may also be isolated as hydrates;depending on the conditions for their formation and/ or the number oftertiary amino groups present in the molecule monoor poly-quaternaryammonium compounds may be formed.

The invention also comprises any modification of the process wherein acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining step(s) of the process is(are) carried out. It also comprises any new intermediates, which may beformed in one of the procedures outlined hereinbefore.

In the process of this invention such starting materials are preferablyused which lead to final products mentioned in the beginning aspreferred embodiments of the invention.

This is a continuation-in-part application of my application Serial No.771,225, filed November 3, 1958, now Patent No. 2,970,149, which in turnis a continuation-inpart application of my application Serial No.754,526, filed August 12, 1958, now abandoned.

The following examples are intended to illustrate the inventionand arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade.

Example 1 To 650 ml. of a 0.37 molar solution of phenyl lithium inbenzene is added dropwise 24 ml. of dry a-picoline under an atmosphereof nitrogen. -After one hour, a solu tion of 10 g. ofZ-(Z-dimethylaminoethyl)-indan-l-one in 20 ml. of benzene is added whilestirring, and the reaction mixture is allowed to stand at roomtemperature for several days. 50 ml. of water is added while cooling andstirring. The water layer is discarded and the benzene solutionextracted with a solution of 20 ml. of concentrated hydrochloric acid in100 ml. of water.

The acidic extract, containing the2-(2-dimethylaminoethyl)-1-[(2-pyridyl)-methy1]-indan-1-ol, is heated onthe steam bath for one hour, the solution is then cooled, made basicwith aqueous ammonia and then extracted with ether. The ether solutionis dried over sodium sulfate, the solvent is removed, and the residue isdistilled to yield the 2-(Z-dimethylaminoethyl) -3- (2-pyridyl-methyl]-in- The free base is converted to the dihydrochloride by treatment ofan ethanol solution of the former with ethanolic hydrogen chloride andprecipitation of the salt with ether. The hydroscopic2-(2-dimethylaminoethyl)- 3-[(Z-pyridyD-methyl]-indene dihydrochlorideis recrystallized from a mixture of ethanol and ether, M.P. 175- 177".The corresponding maleate, prepared by treating an ethanol solution ofthe base with maleic acid, melts at after recrystallization fromethanol.

By treating an acetone solution of the2-(2-dimethylaminoethyl)-3-[(Z-pyridyl)-methyl]-indene with methyliodidethe dirnethiodide of 2-(2-dimethylaminoethyl)-3-[(2-pyridyl)-methyl]-indene may be obtained. The starting material maybe prepared as follows: 33.2 g. of dihyd-ropyran is slowly added to astirred mixture of 50 g. of a-benzyl-malonic acid and 0.1 g. ofp-toluone sulfonic acid, in 130 ml. of diethylether kept at 30 duringthe addition of the d-ihydropyran. The mixture is stirred for anadditional 15 minutes, then poured on ice, and the ether phase isextracted with aqueous potassium carbonate. After washing with water anddrying over magnesium sulfate, the ether is evaporated under reducedpressure by keeping the temperature below 30 to yield thedi-tetr'ahydropyranyl u-benzyl-ma-lonate. A toluene solution of thisester is gradually added to a 50% toluene solution of 4.86 g. of sodiumhydride while heating and stirring for six hours. A solution of 10.8 g.of 2-dimethylaminoethyl chloride in toluene is added dropwise, and thereaction mixture is refluxed for an additional 48 hours. The toluenelayer is washed with water, dried over magnesium sulfate and evaporatedto yield the ditetnahydropyranyl abenzyl-a-(Z-dimethylaminoethyD-malonate; yield: 32.2 g. of crude material.

A mixture of the resulting ester in 180 g. of polyphosphoric acid isstirred at ll0120 during thirty minutes, and then at during anadditional twenty minutes. The reaction mixture is cooled, poured intoice-water, the acidic phase is neutralized with potassium carbonate andextracted with ether. The ether solution is washed with 15% aqueoushydrochloric acid, the aqueous layer is neutralized with potassiumcarbonate and again extracted with ether. After washing with water,drying over magnesium sulfate, the ether is evaporated to yield the2-(2- dimethylaminoethyl)-indan-1-one, yield: 8 g. of crude material.The hydrochloride of the base melts at 165 after recrystallization froma mixture of ethanol and ether.

Example 2 26 g. of Z-ethyI-pyridine is added dropwise with cooling to 20and in an atmosphere of nitrogen to a stirred solution of 650 ml. of an0.37 molar solution of phenyl lithium in benzene. After two hours asolution of g. of 2-(2-dimethylaminoethyl') -indan-1-0ne in 50 ml. ofdry ether is added over a period of five minutes while stirring andcooling to room temperature. After standing for twenty-four hours theorgano-lithium compounds are decomposed by the addition of 50ml. ofwater with external cooling. After separating the water phase from theorganic solution, the latter is washer several times with 50 ml. ofwater, and then extracted with a mixture of 40 ml. of concentratedhydrochloric acid and 100 ml. of water.

The acidic solution, containing the2-(2-dimethylaminoethyl)-1-[1-(2-pyridyl)-ethyl] -indan-1-ol is heatedon the steam bath for thirty minutes to effect dehydration to thedesired indene derivative. The solution is cooled, made strongly basicwith an aqueous solution of ammonia and then extracted with ether. Theether phase is dried over sodium sulfate, filtered, evaporated and theresidue distilled. At mm. pressure the excess of 2-ethyl-pyridine isremoved, at 120/O.5 mm. some unre-acted 2-(2-di-.methylaminoethyl)-indan-l-one distills and at 165-175/ 0.5 mm. the2-(2dimethyl-aminoethyl)-3-[1-(2-pyridyl)- ethylJ-indene is collected.It may be converted to an aqueous solution of the dihydrochloride bydissolving it in the appropriate amount of dilute hydrochloric acid.

Example 3 To a solution of 1.0 g. of Z-(Z-dimethylaminoethyl)-3-[I-(Z-pynidyl)-ethyl]irrdene in 10 ml. of ethanol is added whilestirring and heating 0.4 g. of maleic acid. On cooling the2-(2-dimethylaminoethyl)-3-[1-(2-pyridyl)-ethyl]-indene maleatecrystallizes, is filtered off, washed with a small amount of ethanol andrecrystallized from ethanol, M.P. 158.

Example 4 To 1.0 g. ofZ-(Z-dimethylaminoethyl)-3-[1-(2-pyridyl)-ethyl]-indene in about 10 ml.of ethanol is added a solution of 0.52 g. of L-tartaric acid in 5 ml. ofethanol. After cooling during a few days in the ice box, a crystallineprecipitate is formed, which is filtered off and recrystallized threetimes from ethanol to obtain complete resolution. The L-tartrate of oneof the optically active forms of2-(2-dimethylaminoethyl)-3-[1-(2-pyridyl)- ethyl]-indene melts at135-137; [a] -106 (in ethanol). By treating an aqueous suspension ofthis salt with ammonia and ether an optically active form of2-(2-dimethylarninoethyl) -3-[ 1-(2-py-ridyl)-ethyl] -indane isobtained, which is converted to the corresponding maleate according tothe procedure of Example 3, [a] +70 (in ethanol).

Example 5 By reacting the lithium compound formed from 22 g. of-picoline and phenyl lithium with 10 g. of2-(2-dimethylaminoethyl)-indan-1-one according to the procedure given inExample 2, the 2-(2-dimethylaminoethyl)- 3-[(4-pyridyl)-methyl]-indene,B.P. 165l70/0.7 mm., is obtained after dehydration of the intermediarilyformed 2 (2 dimethylaminoethyl) 1 [(4 pyridyl) methylJ-indan-l-ol. Itcan be converted into its maleate according to the procedure describedin Example 3.

12 Example 6 To a solution of 3 g. of potassium hydroxide in ml. 0.methanol is added'7 g. of 2-(2-dimethylaminoethyl)- in lenehydrochloride and then 7 ml. of 3-pyridine carboxaldehyde, whilestirring and cooling to room temperature. After standing at thattemperature over night, the greater part of the solvent is removed bydistillation under reduced pressure, water is added and the crude2-(2-dimethylaminoethyl)-1-[ (3-pyridyl)-methylidene1-indene isextracted with ether.

The solvent is removed by distillation and the residue is dissolved in50 ml. of ethanol and hydrogenated over 0.5 g. of palladium on charcoal(10%) until one mole of hydrogen is absorbed in about one hour. Thereaction mixture is filtered, the solvent removed under reduced pressureand the residue dissolved in 10 ml. of benzene. The benzene solution ischromatographed on 100 g. of aluminum oxide (basic, activity I).Cyclohexane elutes the desired 2- Z-dimethylaminoethyl -3-[ (3-pyridyl)-methyl]-indene, which is distilled at 160170/0.5 mm. It may beconverted into its maleate according to the procedure of Example 3.

The starting material used in the above procedure may be prepared asfollows: To a solution of 35 g. of 2-(2-dimethylaminoethyl)-indan-1-onein 100 ml. of ethanol is gradually added 10 g. of sodium borohydridewhile stirring. The reaction mixture is refluxed for two hours, then thegreater part of the ethanol is removed by distillation and the residuediluted with water. The 2-(2-dimethylaminoethyl)-indan-1-ol is extractedwith ether and the crude base obtined after removal of the solvent; itspicrate melts at 169-170".

A solution of the crude base iin 350 ml. of glacial acetic acid and ml.of concentrated hydrochloric acid is refluxed for one-half hour, andmost of the solvent then distilled under reduced pressure. The residueis diluted with waer, made basic with ammonia and ext acted with ether.0n addition of 6 N ethanolic hydrogen chloride to the ether solution the2-(2 dimethylaminoethyl)-indene hydrochloride precipitates and isrecrystallized from ethanol, M.P. 202-205.

Example 7 To a stirred suspension of 14 g. of lithium in 400 ml. of dryether is added about 10 ml. of a mixture of 159 g. of bromo-benzene in200 ml. of d y ether. The reaction is carried out in the atmosphere ofnitrogen. The additional bromobenzene solution is given to the reactionin such a rate as to maintain the latter.

A total of 80 g. of Z-ethyl-pyridine, dried over calcium hydride, isthen added dropwise at 20 while stirring. After standing at roomtemperature for four hours an ether solution of 50 g. of2-(2-dimethylaminoethyl)-indanl-one is added while stirring and coolingto room temperature, at which temperature the reaction is allowed tostand for three days. After filtration and dilution with ether, theorganic solution is washed three times with water and then extractedwith 15% aqueous hydrochloric acid.

The acidic solution, containingZ-(Z-d'methylaminoethyl)-1-[(Z-pyridyl)-ethyl]-indan-1-ol, is heated onthe steam bath for one-half hour. After cooling the solution is basifiedwith aqueous ammonia and extracted with ether. The2-(2-dirnethylaminoethyl)-3-[1-(2-pyridyl)- ethylJ-indene is obtainedafter washing, drying and evaporating the solvent and distillation;yield: 23 g.

Example 8 A solution of 17 g. of 2-propylpyridine in 50 ml. of ether isadded over a period of 15 minutes to a sti'red solution of 8 g. of butyllithium in 50 ml. of hexane in an atmosphere of dry nitrogen. Afterthree hours a solution of 13 g. of 2-(2-dimzthylaminoethyl)-indan-l-onein 50 ml. of ether is added over a per'od of fit een minutes whilestirring. The reaction mixture is allowed to stand for two days at roomtemperature; 50 ml. of water is then added dropwise, the aqueous layeris separated and the organic phase is extracted with 60 ml. of 6 Naqueous hydrochloric acid.

The acid extract, containing the 2-(2-dimethylamino-'ethyl)-1-[1-(2-pyridyl)-propyl]-indan-1-ol, is heated on the steam bathfor one hour, cooled, basified with aqueous ammonia and extracted withether. The ether is removed by distillation andthe'2-(2-dimethylaminoethyl)- 3-[l-(2-pyridyl)-propyl]indene isdistilled, 3.1. 165- '175/0.5 mm. The monomethiodide ofZ-(Z-dimethylaminoethyl)-3- [1-(2pyridyl)-propyl]-indene, MP. 255(decomposition) after recrystallization from water, is prepared byreacting the free base in ethanol with methyl iodide.

Example 9 day at room temperature and then worked up as dcscribed inExample 8. The dehydration product of the intermediarily formed 2-(Z-dimethylamindethyl)-1-[dimethyl-(Z-pyridyl)methyl] indane 1-ol,' isdistilled to distilled to yield the desired 2-. (2-dimethylaminoethyl)-3- [dimethyl- (2-pyridyl) -n1ethyl]--inder1e, ;B. P. '155-160 Themethiodide 2 2 -dimethylaniirioethyl)-3-[dimethyl-(2-pyridyl):methylj-indene prepared according to I thepreviously given procedure, melts at 23 4 (with de- 1 composition)- after recrystallization from ethanol.

. v e i y To a stirred solution of- 10.7 g. of -2,6-lutidine in aml. ofether in anatrnosphere of dry nitrogen is added 'dropwise and over aperiod of three hours 50 ml. of an ether solution ;of phenyl lithium,prepared from 1.75 g.

of lithium and 20 g. of bromobenzene according to the proceduredescribed in- Example .7, after standing for an additional two hours atroom temperature, 15, g. of 2- (Z-dimethylaminoethyl)-indan-1-one in 50ml. of ether is added and thereaction mixture is allowed to stand atroom'tempe'rature. It is worked up as described in Example 8; the2-(2-dimethylaminoethyl)-3-[(6-methyl-2- pyridyl)-methyl]-indene, B.P.150155/0.4 mm. is obtained after dehydration of the intermediarilyformed2- (Z-dimethylaminoethyl)-1-['(6methyl 2 4 pyridyl) rnethh yl]-indan1-olwith hydrochloric acid.

Example 11 By reacting the lithium compound of a-picoline with dene ispurified by distillation.

The starting material used in the above reaction may beprepared as.-follows: To a warm suspension of 22 g. of

sodium hydride in 1,000 ml. of toluene is added dropwise while st'rring100 g. of diethyl a-benzyl malonate. The reaction mixture-is refluxedfor one hour after completion of the addition, then a solution of 70 g.of 2-diethylarriinoethyl-chloride in toluene is added and the reactionmixture is refluxed overnight. The toluene solutionis extracted withaqueous hydrochloric acid, the acidic layer is made basic with aqueousammonia and the organic material is extracted with ether. The ethersolution is washed, dried'and evaporated under reduced 14 pressure toyield 136 g. of diethyl a-benZyI-a-(Z-diethylaminoethyl)-malonate, theoxalate of which melts at 117119.

A mixture of 136 g. of diethyla-benzyl-a-(Z-diethylaminoethyl)-malonate, 65.5 g. of potassiumhydroxide, ml. of water and 340 ml. of ethanol is refluxed for 4 hours,then concentrated under reduced pressure. The solid residue is dissolvedin a minimum amount of water, the

aqueous solution is neutralized with acetic acid while externallycooling and the resulting a-benzyl-a-(2-diethyl- .aminoethyD-malonicacid is filtered off and washed with ice Water and ethanol. After dryingunder reduced pressure, it melts at 128; yield: 103 g.

103 g. of e-benzyl-a-(Z-diethylaminoethyl)-malonic acid is heatedto 180with occasional stirring until foam- .ing ceases; the decarboxylation iscomplete after approximately '15 minutes; The resulting melt is cooledand diluted with about 15 ml. of ethanol, ether is added and the'2-benzyl-4-diethylaminob' tyric acid crystallizes, M.P .'102-104;yield: 83 g.

83 g.-of 2-benzyl-4-diethylamino-butyric acid is added :to 415 g. ofpolyphosphoric acid kept at--l20. The temperature is then raised to140-145 for about 20 minutes and the acid is decomposed by pouring thereaction 'mixture'into ice water and neutralizing theaqueous $01111:tion with potassium carbonate.

The 2-(2-diethylaminoethyl)-indan-1-one is extracted with ether, theether solution is washed and dried and the other is evaporated. The

hydrochloride salt, prepared according to the previously givenprocedure, melts at 164-166; yield: 12.3 g.

' Example 12 The 5-chloro-2-(Z-dimethylaminoethyl)-3-[(2 pyridyl)-methyl]-indene, purified by distillation, may be obtained by treatmentof 6-chloro-2-(2dimethylaminoethyl) indanl-one with the lithium compoundof a-picoline according to the procedure outlined in Example 1, wherebythe intermediarily formed 6-chloro-2-(Z-dimethylaminoethyl)-1-[(2-pyridyl)-methyl]-indan-1-ol is dehydrated by heating the acidicextract of the reaction product.

The starting material used in the above reaction may be prepared asfollows: 70 g. of diethyl a-(4-chlorobenzyl)-malonate, B.P. 15'1/0.5mm., obtained by reacting 4-chlorobenzyl chloride with sodium diethylmalonate, is added to a stirred suspension of 8 g. of sodium hydride in500 ml. of refluxing toluene. After 2 hours, 34 g. ofZ-dimethylaminoethyl chloride is added dropwise and the mixture isrefluxed for an additional 12 hours, then cooled and extracted with anexcess of hydrochloric acid. The acidic extract is treated with aqueousammonia and diethyl a (4 chlorobenzyl)-a-(2-dimethylami-noethyD-malonateis separated in aseparatory funnel. It is characterized as thecrystalline oxalate which melts at -178 after recrystallization from amixture of ethanol and ether. Q

The diethyl ot (4 chlorobenzyl)-a- (2-dimethylaminoethyl)-malonate ishydrolyzed with potassium hydroxide as described in Example 4, theresulting a-(4-chlorobenzyl)-a-(2-dimethyl-aminoethyl)-malonic acidmelts at 181 after recrystallizing from water. The2-(4-chlorobenzyl)-4-dimethylamino-butyric acid is obtained bydecarboxylating the malonic acid derivative at a temperature of 185 for5 minutes, and is obtained in crystalline form from ether. It iscyclized as described in Example 11 by treatment with polyphosphoricacid to yield the desired 6 -r chloro 2(2-dirnethylaminoethyl)-indan-1-one which is converted to itshydrochloride, 175-176.

' (N)-ethyl]-indan-1-ol, obtained by reacting the lithium compound ofa-picoline with 2-[2-pyrrolidino-(N) -ethy1]- indan-1-one according tothe procedure of Example 1,

with aqueous hydrochloric acid for one hour the..3-[(2- of diethylmalonate at 50.

pyridyl methyl] -2 [Z-pyrrolidino- (N) -ethy1] -indene can be obtainedand purified by distillation.

The starting material may be prepared as follows: To a cooled solutionof the sodium diethyl a benzyl-malonate, prepared from 75 g. of diethyla-benzyl-malonate and 16 g. of a lzl-mixture of sodium hydride andmineral oil, in 150 ml. of toluene is added a toluene solution of2-pyrrolidino-(N)-ethyl chloride. This solution is prepared by shaking61 g. of 2pyrrolidino-(N)-ethyl chloride hydrochloride in 200 ml. oftoluene with 50 ml. of water containing 23 g. of sodium hydroxide,drying the organic solution over potassium hydroxide pellets and usingit without further purification. The reaction mixture is heated at 120for 6 hours while stirring. The organic solvent is then evaporated underreduced pressure and the residueis refluxed for 7 hourswith a solutionof 40 g. of sodium hydroxide in 200ml. of water and 300 m1. of ethanol.The mixture is acidified with concentrated aqueous hydrochloric acid andevaporated to dryness under reduced pressure. The remaining residue isheated in an oil bath with the temperature slowly raising. at 180 overabout one hour; the decarboxylation is complete after'30'minutes heatingat this temperature; Themixture is digested with 250 ml. of hotethanoL-the hot solution is filtered and thesolvent is evapora-ted todryness to give the crystalline 1 2 benzyl 4-pyrrolidino-(N)-butyricacid hydrochloride, M.P. 178-182 The resulting acid hydrochloride isadded in small quantities while stirring to 400 g. of polyphosphoricacid kept at 100. The temperature is-then raised to 120 and held for 30minutes; the mixture is then poured onto ice, made alkaline andextracted with ether. After the removal of the organic solvent, the2-[2-pyrrolidino-(N) ethyl]- indan-l-one is distilled at 148-1S2/ 0.4mm.

Example 14 The reaction of the lithium compound of 2-ethyl-pyridine with2 [2 (4-methyl-l-piperazino)-ethyl]-indan-lone according to theprocedure of Example 7 furnishes the2-[2-(4-methyl-l-piperazino)-ethyl]-1-[1-(2-pyridyl)- ethyl]-indan-l-ol,which is dehydrated by heating with aqueous hydrochloric acid to thedesired 2-[2-(4-methyll-piperazino) ethyl] -3-[ 1- 2-pyridyl) ethyl]-indene, purified by distillation.

The starting material may be prepared according to the procedure givenin Example 13 by using the same quantities of startingmaterial, andreplacing 2-pyrrolidino- -(N)-ethyl chloride by 2 (4methyl-l-piperazino)-ethyl chloride. The intermediate2-benzyl-4-(4-methyl-l-piperazino)-butyric acid hydrochloride melts at195200 and is cyclized to the 2 [2 (4smethyl-l-piperazino)-ethylindan-l-one, B.P. 168-170/ 0.4 mm.

Example 15 ,ing the 2-(Z-dimethylaminoethyl)-6-methoxy-1-[(2-pyridyl)-methyl]-indan-l-ol, is dehydrated by heating with :aqueoushydrochloric acid to yield the 2-(2-d1methyl- :arninoethyl) methoxy 3[(2 pyridyl) methyl]- findene, which is purified by distillation and maybe converted into the maleate according to the procedure of .Example 3..

The starting material used in the above reaction may be prepared asfollows: To a solution of 16.25 g. of sodium in 288 ml. of ethanol isslowly added 113.5 g.

The clear reaction solution is treated dropwise with 110.7 g. of4-methoxybenzyl chloride and the reaction mixture is refluxed for onehour. the residue is diluted with water and the-oily product-- Afterfiltration and evaporation of the solvent,

16 is extracted with ether, the ether solution washed and dried, and thesolvent evaporated. The diethyl a-(4- methoxybenzyl)-malonate isdistilled, B.P. 155l65/ 0.75 mm.; yield: 667 g.

To a refluxing suspension of 6.1 g. of sodium hydride in 550 ml. oftoluene is added dropwise while stirring 66.7 g. of diethyla-(4-methoxybenzyl)-malonate and the reaction mixture is refluxed forone hour. A solution of 31 g. of Z-dimethylarninoethyl chloride intoluene is added, the reaction mixture heated overnight and the toluenesolution then extracted with aqueous hydrochloric acid. The acidic layeris made basic with aqueous ammonia, the organic material is extractedwith ether, the ether solution is washed and dried and the solventevaporated. 77 g; of diethyl a-(4-methoxybenzyD-u-(2-dimethylaminoethyl)-malonate is obtained and characterized as thehydrochloride salt, 145-l47.

A mixture of 73.4 g. of diethyl t-(4-1nethoxybenzyl)-a-(2-dimethylaminoet hyl)-malonate, 26.8 g. of potassium hydroxide,30,jml. of water'and 148 ml. of ethanol is refluxed for 4 hours and thenconcentrated under reduced pressure. The solid residue is dissolved in aminimum amount of water and neutralized with acetic acid under externalcooling. The resulting u-(4-methoxybenzyD-u-(Z-dimethylaminoethyl)-malonic acid is filtered off, washed with icewater and ethanol and dried under reduced pressure, M.P. 163-165 yield:45.5 g.

45.5 g. of e-(4-methoxybenzyl)-a-(2-dimethylaminoethyl)-malonic acidisheated to 180 with occasional stirring until foaming-ceases aftercompletion of decarboxylation. The resulting melt is diluted with about10 ml. of ethanol, ether is added, and the2-(4-methoxybenzyl)-4-dimethylamino-butyric acid crystallizes, M.P. 87;yield: 33.7 g.

33.7 g. of 2-(4-methoxybenzyl)-4-di-methylamino-butyric acid isgradually added to 168 g. of polyphosphoric acid kept at -1-20, andthe'reaction mixture is heated to -150 for 20 minutes. It is then pouredinto ice water, neutralized with potassium carbonate, and, since nocrystalline product is formed, is made strongly basic with 3 N aqueoussodium hydroxide. The organic material is extracted with ether, theether solution washed and dried and the solvent then evaporated. Theresulting 2-(2-dimethylaminoethyl)-6-methoxy-indan-1-one is converted tothe hydrochloride, M.P. 225-227; yield: 14.5 g.

Example 16 A solution of Z-(Z-dimethylaminoethyl)-indan-l-one in etheris added to a Grignard reagent prepared from 2-pyridyl ethyl bromide andmagnesium in ether. The reaction mixture is allowed to stand at 5; thelarger part of the ether is then removed by distillation and thesomewhat viscous residue is refluxed for several hours. The mixture isdiluted with ether and decomposed with aqueour ammonium chloride. Theseparated ether solution is evaporated to leave the oily2-(2-dimethylaminoethyl)- l-[2-(2-pyridyl)-ethyl]-indan-l-ol, which isdehydrated by refluxing with a mixture of acetic acid and concentratedaqueous hydrochloric acid. The acids are then removed by distillationunder reduced pressure, the residue is diluted with water, basified andextracted with ether. The ether extract is evaporated to dryness, a fewmilliliters of benzene are added to the residue, which ischromatographed on aluminum oxide. The 2-(2-di-methylaminoethyl) 3 [2 (2pyridyl) ethyl] indene can be eluted and may be converted to themaleate.

Example 17 The reaction of 2-(2-dimethylaminoethyl)-3-methylindan-l-onewith the lithium compound of 2-ethylpyridine according to the procedureof Example 7 furnishes the 2 (2 dimethylaminoethyl) 3 methyl 1 [1 (2pyridyl)-ethyl]indan-1-ol, which is dehydrated to the desired 2 (2dimethylaminoethyl) 1 methyl 3 [l- (Z-pyridyD-ethyljindene by treatmentwith warm aqueous hydrochloric acid.

The starting material used in the above reaction may be prepared asfollows: To a solution of 12.3 g. of sodium in 200 ml. of ethanol keptat 50 is slowly added 81 ml. of diethyl malonate, followed by dropwiseaddition of 100 g. of l-phenylethyl bromide. The reaction mixture isrefluxed for about one hour, the resulting sodium chloride is filteredoff and the solvent is evaporated. The residue is distilled to give 83g. of diethyl a-(l-phenylethyl)-malonate, 3.1. 165170/ 18 mm.

The diethyl o-(1-phenylethyl)-malonate is slowly added to a heatedsuspension of 17.5 g. of sodium hydride (1:1- rnixture in mineral oil)in 750 ml. of toluene; the reaction mixture is refluxed for one hour anda toluene solution of 55 g. of 2-dimethylaminoethyl chloride is added.The reaction mixture is refluxed overnight and then extracted with 15%aqueous hydrochloric acid; the acid solution is made basic with ammoniaand extracted with ether. The ether is removed to yield 93 g. of thedesired diethyl a-(Z-dimethylaminoethyl)-u-( l-phenylethyl)-malonate,the oxalate of which melts at 136-138".

This ester is hydrolyzed by refluxing with 27.7 g, of sodium hydroxidein 45.5 ml. of water and 186 ml. of ethanol for 8 hours. Afterevaporation of the organic solvent, a minimum amount of water is addedto complete solution whereupon the hydrochloride is formed by theaddition of concentrated aqueous hydrochloric acid. The water isevaporated under reduced pressure and the residue is treated withboiling ethanol to extract the hydroch oride salt. The separated organicsolution is evaporated and the residue is decarboxylated by heating at150 for 15 minutes and then raising the temperature to 180-l90 untilfoaming ceases. The non-crystalline residue is dissolved in a minimumamount of hot ethanol and poured onto a suspension of filter-eel inethanol. The mixture is filtered and added to 600 g. of polyphosphoricacid at a temperature of 85 while vigorously stirring. The reactiontemperature is kept at 9095 during the addition and then raised to95-100 for 20 minutes. After cooling, it is poured onto ice, thesolution is filtered and the filtrate neutralized with potassiumcarbonate. The desired Z-(Z-dimethylaminoethyl)-3-methylindan-l-one isextracted with ether and distilled after the evaporation of the organicsolvent, B.P. 135/ 1 mm.; yield: 31.5 g.

Example 18 A solution of 15 g. of dry Z-ethyl-pyridine in 25 ml. of drybenzene is added to a solution of 60 ml. of butyl lithium in hexane(containing 0.154 g. lithium per ml.) under cooling to 25 and in anatmosphere of dry nitrogen. After three hours 12 g. ofZ-(Z-dimethylarnino-Z- methyl-ethyl)-indan-1-one in 25 ml. of benzene isadded at 25 The reaction mixture is allowed to stand for seven days atroom temperature, 100 ml. of water is added dropwise to decompose theorganic lithium salts and the water layer is separated. The remainingorganic phase is extracted with 75 ml. of 4 N aqueous hydrochloric acid.

The acidic solution, containing the 2-(2-dimethylamino- Z-methyl-ethyl)1 [1 (2-pyridyl)-ethyl]-ir1dan-1-ol, is heated on the steam bath forthirty minutes and is then made basic with aqueous ammonia. Afterextraction with ether the organic layer is separated, dried over sodiumsulfate and then evaporated. The remaining residue is distilled underreduced pressure and the fraction, boiling at 165170/0.2 mm., iscollected. This fraction is a mixture of approximately equal amounts ofthe two racemates of 2-(Z-dimethylamino-Z-methylethyl) -3- 1- 2-pyridyl-ethyl] -indene.

Salts of this mixture can be prepared according to the procedure givenin Example 3.

The two racemates of the above mixture of racemates may be separated asfollows: 5 g. of the mixture is dis- I8 solved in 20 ml. of ethanol and3 ml. of methyl iodide is added. Within ten minutes one of the racematesof 2-(2-dimethylamino 2 methyl-ethyl)-3-[1-(2-pyridyl)- ethyl]-indenemethiodide crystallizes and is separated by filtration, M.P. 215(decomposition). The second racemate methiodide, which isnon-crystalline, can be collected by evaporating the solvent. Thedistillation of the separated methiodides at 170/0.2 mm. yields thesingle racemates of 2-(2-dimethylamino-2-methyi-ethyl)- 3- 1- Z-pyridyl)-ethyl] -indene.

The starting material used in the above reaction may be prepared asfollows: 300 g. of diethyl a-benzylmalonate is added over a period ofthirty minutes to a refluxing suspension of 66 g. of sodium hydride inmineral oil (50% sodium hydride) in 2000 ml. of toluene. After refluxingfor one hour a solution of 2-dimethylamino-2- methyl-ethyl chloride intoluene (prepared by dissolving 310 g. of 2-dimethylamino-Z-methyl-ethylchloride hydrochloride in 600 ml. of water, basifying the aqueoussolution and extracting it with 1000 ml. of toluene, which solution isdried over sodium sulfate) is added over a period of one hour. Afterrefluxing overnight the reaction mixture is cooled and extracted withaqueous hydrochloric acid. The acidic extract is basified with ammoniaand the separating oil is extracted with ether. After drying the etheris evaporated, leaving 396 g. of diethyl Ot-bBIIZYl 0c (2dimethylamino-Z-methyl-ethyl)- malonate as a residue.

g. of diethyl a-benzyla-(Z-dimethylamino-Z- methyl-ethyl)-malonate isadded to 840 g. of polyphosphoric acid at 100 while stirring. Thetemperature is raised slowly to 160 and held for thirty minutes. Aftertreatment with ice Water the reaction mixture is made basic withpotassium carbonate and extracted with ether. The ether is evaporated toyield a residue containing as the main constituent theZ-(Z-dimethylamino- Z-methyl-ethyl)-2-carbethoxy-indan-l-one. 75 g. ofthis residue is refluxed with 650 ml. of 2 N aqueous hydrochloric acidfor four hours. The acidic solution is made basic with ammonia, theorganic material is extracted with ether, the ether evaporated and theresidue distilled at 112ll4/ 0.23 mm. This fraction is converted to thehydrochloride with ethanolic hydrogen chloride and the crystallinematerial is recrystallized from ethanol, M.P. 194-196. Thishydrochloride yields the pure 2-(2-dimethylamino-Z-methyl-ethyl)-indan-1-one by treatment with ammonia.

Example 19 The 3-[(2-pyridyl)-lower .alkylJ-Z-(tertiary aminoloweralkyD-indene compounds may be made up into pharmaceutical preparations.Thus, Z-(Z-dimethyiaminoethyl) -3-[I-(Z-pyridyl)-ethyl1-indene maleatemay be formulated into tablets containing 0.002 g. of the antihistaminecompound, as follows (for 2,800 tablets):

All ingredients are screened through a No. 40 mesh stainless steelscreen into a mixer and mixed for thirty minutes. They are compressedinto tablets weighing 0.175 g. by employing standard concave punches anddies.

Injectable solutions, containing 1 rag/ml. of2-(2-dimethylaminoethyl)-3-[1-(2-pyridyl)-ethyl] indene, may be preparedas follows (for 1000 ml.):

Ingredients:

2 (2 dimethylaminoethyl)-3-[l-(2-pyridyl)-ethyl]-indene maleate g 1.000Lactic acid g 18.000 Sodium hydroxide g 4.140 Sodium chloride g 1.520Sodium sulfite g 1.000 Disodium salt of ethylenediamine-tetracetic acid-g 0.100 Water for injection, q.s ml 1000.000

The lactic acid and the sodium hydroxide are added to 40 ml. of waterfor injection, and the disodium salt of ethylenediamine-tetracetic acid,the 2-(2-dimethylaminoethyl)-3-[1-(2-pyridyl)-ethyl]-indene maleate, thesodium chloride and the sodium sulfite are added in this order. Nitrogengas is passed through the solution for 30 minutes, which is thenfiltered through a medium porosity sintered glass filter. The solutionis filled into ampuls, which are sterilized in an autoclave at poundsper square inch pressure and at 115 C. for thirty minutes.

An additional possibility to introduce a (2-pyridyl)- lower alkylradical into a 2-(tertiary amino-lower alkyl)- indan-l-one compoundcomprises reacting the latter with the alkali metal salt of an alkalimetal (2-pyridyl)-lower alkanoate, and treating the resulting productwith an acid. An alkali metal salt of an alkali metal (2-pyridyl) loweralkanoate is, for example, the lithium, sodium or potassium salt formedby treating a sodium (2-pyridyl)- lower alkanoate with an alkali metalamide or hydride, e.g. lithium, sodium or potassium amide or hydride, orwith a monocyclic aryl alkali metal compound, e.g. phenyl lithium orphenyl sodium, in an inert solvent such as an ether, e.g. p-dioxane, anaromatic hydrocarbon, e.g. benzene, toluene or xylene, or liquidammonia. The reaction of a 2-(tertiary amino-lower alkyl)-indan-1-onecompound with an alkali metal salt of an alkali metal (2-pyridyl)-loweralkanoate is preferably carried out in the presence of a solvent, forexample, p-dioxane. A resulting intermediate may not be isolated, buttreated directly with an acidic reagent, such as an aqueous solution ofan inorganic acid, for example, a mineral acid, e.g. hydrochloric orsulfuric acid, if desired, at an elevated temperature, to yield thedesired 3-[(2-pyridyl)- lower alkyl]-2-(tertiary amino-loweralkyl)-indene.

A third generally applicable method to, prepare the indene compounds ofthis invention comprises introducing the tertiary amino group or thetertiary amino-lower alkyl radical into a Z-(reactive esterifiedhydroxy-lower alkyl)-3-[(2-pyridyl)-lower alkyl]-indene or into a 1-[(2-pyridyl-lower alkyl]-indan-2-one, respectively.

For example, by treating a 2-(reactive esterified hydroxy-loweraIkyD-indene, which contains in the 3-position a (2-pyridyl)-lower alkylradical, with a secondary amine or a salt thereof, the correspondingZ-(tertiary amino-lower alklyl)-indene compounds of this invention maybe formed. A reactive esterified hydroxyl group is, for example, ahydroxyl group esterified with a strong inorganic acid, such as amineral acid, e.g. hydrochloric, hydrobromic, hydriodic or sulfuricacid. The preferred starting materials are 2-(halogeno-loweralkyl)-indenes, which contain in the 3-position a (2-pyridyl)-loweralkyl radical; secondary amines are those which furnish the tertiaryamino groups described in detail hereinabove. The reaction is preferablycarried out in the presence of a solvent, such as a lower alkanol, e.g.methanol, ethanol, propanol, isopropanol or higher homologs; ahydrocarbon, such as an aromatic hydrocarbon, e.g. benzene or toluene,or a halogenated aliphatic hydrocarbon, e.g. chloroform, and/or, ifdesired, in the presence of an acid neutralizing reagent, such as analkali metal hydroxide, e.g. sodium hydroxide, or an alkali metalcarbonate, e.g. sodium or potassium carbonate or hydrogen carbonate. Thereaction may be completed by elevating 20 q the temperature, forexample, to the boiling point of the used solvent.

A Z-(reactive esterified hydroxy-lower alkyl)-indene compound, whichcontains in the 3-position a (2-pyridyl)- lower alkyl radical, and whichis used as the starting material in the above reaction, may be prepared,for example, by reacting an alkali metal, e.g. sodium, salt of an:x-benzyl-malonic acid ester, such as one of those out-- linedhereinbefore, with an etherified hydroxy-lower alkyl halide. Anetherified hydroxyl group is particularly a.- lower alkoxy group, e.g.methoxy or ethoxy, or a mono-- cyclic aryloxy group, e.g. phenoxy; ahalide is particu-- larly a chloride or a bromide. The resultinga-benzyl-m- (etherified hydroxy-lower alkyl)-malonic acid ester isthencyclized, if desired, prior to or after hydrolysis and].

decarboxylation, to a Z-(etherified hydroxy-lower alkyl)-- indan-l-one,according to known methods. The (2- pyridyl)-lower alkyl radical is thenintroduced into the indan-l-one compound according to one of thepreviously described methods. The resulting 3-[(2-pyridyl)-lov.'eralkyl]-2-(etherified hydroxy-lower alkyl)-indene, which may be obtainedafter subsequent dehydration of an intermediarily formed indan-l-olcompound, is treated with an ether splitting reagent, for example, amineral acid, such as a hydrohalic acid, e.g. hydrochloric orhydrobromic acid. The Z-(reactive esterified hydroxyloweralkyl)-3-[(2-pyridyl)-lower alkyl]-indene may be obtained directly upontreatment with the acid reagent, or may be formed by treatment with areagent capable of converting a hydroxyl group into a reactiveesterified hydroxyl group, for example, with a thionyl halide, e.g.thionyl chloride, which reaction may, if desired, be car ried out in aninert solvent, such as an aromatic hydro carbon, e.g. benzene ortoluene.

This reaction and/or the sequence of the steps may be modified; forexample, the alkali metal salt of an a-benzyl-malonic acid ester may betreated with a lower alkylene oxide, e.g. ethylene oxide, to form ana-benzyl-u- (hydroxy-lower alkyl)-malonic acid ester, e.g.a-benzylu-(2-hydroxyethyl)-malonic acid ester, which may be hydrolyzed,decarboxylized and cyclized to a Z-(hydroxylower alkyl)indan-1-onecompound, in which the hydroxy group is separated from the 2-position ofthe indan nucleus by at least two carbon atoms. A resulting indanl-onecompound is then converted into the desired 2- (reactive esterifiedhydroxy-lower alkyl)-3-[2-pyridyl)- lower alkyl]-indene derivative, forexample, by introducing a (2-pyridyl)-lower alkyl radical according toone of the previously described procedures. The free hydroxyl group isthen converted into the reactive esterified hydroxyl group, for example,by treatment with a thionyl halide, e.g. thionyl chloride. These stepsmay also be performed in reversed order.

Furthermore, certain starting materials of the above reaction may alsobe obtained by reacting an indan-2-one with an etherified hydroxy-loweralkyl-Grignard reagent, dehydrating the resulting indan-2-ol compound tothe 2- (etherified hydroxy-lower alkyl)-indene, into which the(2-pyridyl)-lower alkyl radical may be introduced according to one ofthe previously outlined procedures. The ether group may then be split bytreatment with an acid; the resulting free hydroxyl group is convertedinto a reactive esterified hydroxyl group, and any additional doublebond present may be reduced; these steps may be carried out in anyorder.

A tertiary amino-lower alkyl group may be introduced into al-[(2-pyridyl)-lower alkyl]-indan-2-one compound according to previouslydescribed methods, which are used for the introduction of a(2-pyridyl)-lower alkyl radical into a 2-(tertiary amino-loweralkyl)-indan-1-one. For example, the indan-Z-one compound may be reactedwith a tertiary amino-lower alkyl metal halide according to the Grignardprocedure, and a resulting 1-[ (2-pyridyl)- lower alkylJ-Z-(tertiaryamino-lower alkyl)-indan-2-ol may be converted into the desired indenecompound by 21 dehydration, for example, with an acid, such dehydrationbeing carried out according to previously described methods.

The 1-[(2-pyridyl)-lower alkyl]-indan-2-ones, which are used as startingmaterials in the above reaction may be prepared by introducing into anindan-Z-one the (2- pyridyl)-lower alkyl radical according to previouslydescribed procedures. For example, by reacting a 2-pyridinecarboxaldehyde with an indan-Z-one compound in the presence of a base a1-[(2-pyridyl)-methyl-idene1-indan-2-one may be obtained, which may beconverted into the desired 1-[(2-pyridyl)-methylidene]-indau-2-one byreductive removal of the double bond, if desired, with subsequentreoxidation of any reduced oxo group.

The 3-[(4-pyridyl)-lower alkyl] -2-(tertiary amino-lower alkyl)-indenesmay be obtained according to the above procedures by using theappropriate starting materials yielding such 4-pyridyl derivatives. Or,reactants containing 3-pyridyl radicals may be utilized to prepare thedesired 3-[(3-pyridyl)-lower alkyl]-2-(tertiary amino-loweralkyl)-indenes.

In the resulting indene compounds functional groups attached to thearomatic portion of the indene nucleus may be converted into otherfunctional groups: a nitro group may be reduced to an amino group; anitro or a primary amino group may be reductively alkylated to formsecondary or tertiary amino groups; an amino group may be diazotized andconverted to halogen according to the Sandmeyer method; a hydroxyl groupmay be etherified, for example, by treatment with a diazolower alkane,e.g. diazomethane, or esterified to a lower alkanoyloxy group, forexample, with acetyl chloride to an acetoxy group, etc.

What is claimed is:

1. 2-(N,N-di-lower alkyl-amino-lower alkyl)-1-[(3- pyridyl)-methylidene] -indene.

2. 2 (Z-dimethylaminoethyl)-1-[(3-pyridyl)-methylidene]-indene.

3. 2 (N,N-di-lower alkyl-amino-lower alkyl)-l-[(2- pyridyl -methylidene]-indene.

4. 2- (N,N-di-lower alkyl-amino-lower alkyl)-1-[(4- pyridyl)-methylidene] -indene.

5. Process for the preparation of 2-(N,N-di-lower alkyl amino-loweralkyl)-3-[(2-pyridyl)-methyl]-indene, which comprises reacting2-(N,N-1ower alkyl-amino-lower alkyD-indene withpyridine-Z-carboxaldehyde in the presence of an alkali metalsalt-forming condensing reagent selected from the group consisting ofalkali metal hydroxide, alkali metal lower alkanolate, alkali metalhydride, alkali metal amide and quaternary ammonium hydroxide andreducing the resulting product with one mole of hydrogen in the presenceof a palladium hydrogenation catalyst.

6. Process according to claim 5, which comprises using palladium oncharcoal as the palladium catalyst.

7. Process for the preparation of 2-(N,N-di-lower alkyl amino-loweralkyl)3-[(3-pyridyl)-methyl]-indene, which comprises reacting2-(N,N-di-lower alkyl-aminolower alkyl)-indene withpyridyl-3-carboxaldehyde in the presence of an alkali metal salt-formingcondensing reagent selected from the group consisting of alkali metalhydroxide, alkali metal lower alkanolate, alkali metal hydride, alkalimetal amide and quaternary ammonium hydroxide and reducing the resultingproduct with one mol and hydrogen in the presence of a palladiumhydrogenation catalyst.

8. Process for the preparation of 2-(N,N-di-lower alkylamino loweralkyl)-3-[(4-pyridyl)-methyl]-indene, which comprises reacting2-(N,N-lower alkyl-amino-lower alkyl)-indene withpyridine-4-carboxaldehyde in the presence of an alkali metalsalt-forming condensing reagent selected from the group consisting ofalkali metal hydroxide, alkali metal lower alkanolate, alkali metalhydride, alkali metal amide and quaternary ammonium hydroxide andreducing the resulting product with one mol of hydrogen in the presenceof a palladium hydrogenation catalyst.

References Cited in the file of this patent UNITED STATES PATENTSHoffman et al. May 4, 1948 Huebner Aug. 2, 1960 OTHER REFERENCES

1. 2-(N,N-DI-LOWER ALLKYL-AMINO-LOWER ALKYL)-1-(3PYRIDYL)-METHYLIDENE!-INDENE.